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Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer
- Source :
- Oncology Reports
- Publication Year :
- 2015
- Publisher :
- Spandidos Publications, 2015.
-
Abstract
- Multikinase inhibitors (MKIs) targeting VEGF receptors and other receptor tyrosine kinases have shown considerable activity in clinical trials of thyroid cancer. Thyroid cancer frequently exhibits activation of the RAS/RAF/MEK/ERK pathway. In other types of cancer, paradoxical ERK activation has emerged as a potential resistance mechanism to RAF-inhibiting drugs including MKIs such as sorafenib and pazopanib. We therefore queried whether the MEK inhibitor trametinib, could augment the activity of pazopanib in thyroid cancer cell lines. Trametinib potently inhibited growth in vitro (GI50 1.1-4.8 nM), whereas pazopanib had more limited in vitro activity, as anticipated (GI50 1.4-7.1 µM). We observed progressive upregulation of ERK activity with pazopanib treatment, an effect abrogated by trametinib. For xenografts (bearing either KRASG12R or BRAFV600E mutations), the combination of trametinib and pazopanib led to sustained shrinkage in tumor volume by 50% or more, compared to pre-treatment baseline. Trametinib also was highly effective as a single agent, compared to pazopanib alone. These preclinical findings support the evaluation of trametinib, alone or in combination with pazopanib or other kinase inhibitors, in thyroid cancer clinical trials. We highlight the importance of pharmacodynamic assessment of the ERK pathway for patients enrolled in trials involving MKIs.
- Subjects :
- Sorafenib
MAPK/ERK pathway
Cancer Research
Indazoles
MAP Kinase Signaling System
Pyridones
differentiated thyroid cancer
Mice, Nude
Pyrimidinones
Pharmacology
BRAF
Pazopanib
angiogenesis
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Thyroid Neoplasms
Extracellular Signal-Regulated MAP Kinases
Thyroid cancer
Cell Proliferation
030304 developmental biology
Trametinib
Sulfonamides
0303 health sciences
Oncogene
business.industry
MEK inhibitor
Cancer
Articles
General Medicine
medicine.disease
Xenograft Model Antitumor Assays
MEK
Tumor Burden
3. Good health
ERK
Pyrimidines
Oncology
030220 oncology & carcinogenesis
Cancer research
Female
business
medicine.drug
Subjects
Details
- ISSN :
- 17912431 and 1021335X
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Oncology Reports
- Accession number :
- edsair.doi.dedup.....14a011380bdb40df26a0a4584ae9ebd5